Selenium (Se) is an essential trace element in human nutrition due to its presence, in the form of selenocysteine residue, in 25 selenoproteins. Selenoproteins participate in diverse biological processes, but their key roles are to regulate cellular redox homeostasis. These redox activities are modulated by the level and chemical form of dietary Se in a selenoprotein- and organ-specific manner. Selenoprotein status has been implicated in a variety of physiological processes and diseases, but the function of Se that attracted the most attention is its role in cancer. There are numerous studies, including clinical trials, which support the role of Se in cancer prevention, but there are also studies that found no such role. The consensus is that Se may be beneficial under conditions of low Se status, when selenoprotein levels are suboptimal, whereas this micronutrient is not effective in cancer prevention when Se levels are above that needed to saturate selenoprotein expression. Our research revealed a dual role the 15 kDa selenoprotein (Sep15) in cancer. We hypothesize that Sep15 and its homolog selenoprotein M (SelM) serve as redox gatekeepers for disulfide-rich proteins that pass through the endoplasmic reticulum. This hypothesis will be addressed using cell culture and mouse models. We will determine redox targets of Sep15 and SelM, characterize consequences of their deficiency, profile immunoglobulins in selenoprotein knockout mice and examine their maturation status. In addition, we found that high-throughput analyses of selenoproteins in a large panel of human cancer cell lines provides direct insights into the functions of these proteins in the context of human cancer, control of redox homeostasis and dependence of various cancer types on selenoproteins. We will characterize the human selenoproteome and selenocysteine machinery for their roles in human cancer by analyzing coexpression patterns and dependence of various cancer types on selenoproteins and drugs, and will link this information with genotype and expression patterns. This information will define the roles of selenoproteins in human cancer and provide critical information for the development of approaches for personalized use of dietary selenium to modulate cancer prevention and progression. Overall, these studies will provide critical insights into the role of selenium and selenoproteins in cancer.